Primary malignant gliomas remain among the most lethal and difficult to treat forms of cancer. Of these, glioblastoma multiforme (GBM) is the most rapidly growing. Despite improvements, the outcome for GBM patients has not changed significantly over the past 30 years. With maximal conventional therapy, survival is approximately 14 months from time of diagnosis and about 30 weeks from the time of recurrence. Recent advances in the understanding of brain tumor biology have led to the development of novel therapeutic approaches, including oncolytic virotherapy. Viruses, particularly adenovirus and HSV have been engineered to deliver therapeutic genes, while other viruses such as parvovirus, measles virus, and reovirus have been utilized for their innate cytotoxic effects without further engineering. Among the non-engineered oncolytic viruses, Newcastle Disease Virus (NDV) has a long history as a broad spectrum oncolytic agent that can destroy tumor cells and stimulate the immune system (Bar Eli, N., et al., J. Cancer Res. Clin. Oncol. 122: 409-415, 1996; Tzadok-David, Y., et al., J. Cancer Res. Clin. Oncol. 121: 169-174, 1995; Schirrmacher, V., et al., Int. J. Oncol. 18: 945-952, 2001). NDV is a single stranded RNA virus, whose natural host is poultry.
NDV strains have been classified as pathogenic (mesogenic or velogenic) or non-pathogenic (lentogenic) to poultry. The 73T, MTH68 and PV701 (MK107) mesogenic strains of NDV have been the subject of several clinical studies. NDV-PV701 has recently been evaluated in a Phase I study of patients with advanced solid tumors; however, patients with CNS tumors were excluded from these studies (Pecora, A. L., et al., J Clin Oncol 20:2251-66, 2002). The anti-neoplastic responses to MTH68 in malignant glioma have been reported (Csatary, L. K., et al. J. Neurooncol. 67: 83-93, 2004).
Lentogenic strains of NDV have also been shown to kill some cancer cell lines (Schirrmacher, V., et al. ibid). Infection of tumor cells by lentogenic NDV has been found to generate several innate danger signals leading to apoptosis. The lentogenic Ulster strain of NDV has been combined with various tumor cells as a tumor vaccine for different cancers including glioblastoma, however the use of a lentogenic NDV strain alone in virotherapy has not been evaluated.
WO 00/62735 of Pro-Virus discloses the use of any interferon sensitive strain of virus for killing neoplastic cells that are deficient in the interferon response. The Pro-Virus disclosure supplies a catalog of viral strains including three mesogenic strains of NDV (MK107, NJ Roakin, and Connecticut-70726) shown to be useful for treatment of human tumor xenografts in athymic mice. NDV administration to these mice caused tumor regression, which was attributed to more efficient and selective replication of NDV in tumor cells versus normal cells. The differential sensitivity of tumor cells to killing by NDV was disclosed to be correlated to an inability of the cells to manifest interferon-mediated antiviral response. The above patent application claims methods of infecting neoplasms or tumors and methods of treating neoplasms or tumors by interferon-sensitive, replication competent RNA or DNA viruses.
European Patent No. 0696326 discloses a use of NDV in manufacturing of a medicament for treatment of cancer, wherein the NDV is of moderate virulence and is cytolytic. European Patent Application No. 1314431 discloses a composition comprising NDV for use in the treatment of cancer, wherein the NDV is of moderate virulence and is cytolytic. European Patent Application No. 01486211 claims a use of NDV in the manufacture of medicament for treatment of cancer in a mammal having a tumor wherein the medicament is administered systematically in multiple doses to said mammal in an amount sufficient to cause tumor regression. Though European Patent Application No. 01486211 refers to various strains of NDV, both cytolytic and non-cytolytic, the applicants of the European application provide in vivo effects of two mesogenic strains of NDV in animal models. No clinical studies nor examples of in vivo effects of lentogenic strains of NDV are disclosed in the European Patent Application No. 01486211.
International Patent Application WO 2005/018580 claims a method of treating a mammalian subject having a tumor comprising administering to the subject an amount of a NDV. Though the NDV according to WO 2005/018580 can be of low (lentogenic), moderate (mesogenic) or high (velogenic) virulence, the application relates to a mesogenic strain of NDV. No clinical studies nor examples of in vivo effects of lentogenic strains of NDV are disclosed in WO 2005/018580.
International Patent Application WO 2003/022202 discloses pharmaceutical compositions comprising a lentogenic oncolytic strain of NDV and methods for treating cancer comprising same. International Patent Application WO 2003/022202 discloses pre-clinical studies that demonstrate the oncolytic activity of a lentogenic strain of NDV.
U.S. Patent Application Publication No. 2004/0131595 discloses a method for treating a mammalian subject having a carcinoid tumor comprising administering to the subject a negative-stranded RNA virus. The negative-stranded RNA virus is a replication competent oncolytic virus, particularly a NDV, and more particularly a mesogenic strain of NDV.
There is still an unmet and urgent need for efficient methods of treating cancer patients. Particularly, there remains an urgent and compelling need for efficient methods of treating cancer patients unresponsive to conventional therapies.